OBJECTIVE: To conduct a multicenter randomized controlled trial of the efficacy of standardized Chinese herbal medicines(CHMs) against acuteon-chronic liver failure(ACLF) and provide reproducible and high-level evidence for clinical practice.METHODS: This is a prospective, multicenter, centrally randomized controlled trial. Patients diagnosed with hepatitis B virus-related ACLF(n = 510)will be allocated to the standard medical therapy or CHM group at a 1∶1 ratio. Two CHMs will be used on the basis of the traditional Chinese medicine syndrome: Liangxue Jiedu granules for excess syndromes and Yiqi Jiedu granules for deficiency syndromes. The primary outcome is transplant-free survival at week 12. The secondary outcomes are(a)transplant-free survival at week 24,(b) liver function as assessed using the model for end-stage liver disease score at week 12,(c) liver function as assessed using the Child-Pugh score at week 12, and(d) the incidence of complications at week 12.DISCUSSION: The effectiveness and safety of CHM formulations will be assessed following treatment for ACLF.TRIAL REGISTRATION: The trial was registered at Clinical Trials.gov(NCT03577938) on June 24, 2018.